Heteroaroyl-benzindolyl acids



United States Patent 3,336 307 HlEJTEROAROYL-BEDIZINDOLYL ACIDSTsung-Ymg Shen, Westfield, N.J., assignor to Merck & Co., Inc., Rahway,N.J., a corporation of New Jersey No Drawing. Filed Mar. 29, 1965, Ser.No. 443,717 4 Claims. (Cl; 260--247.2)

This application is a continuation-in-part of my copending application,Ser. No. 306,712, filed Sept. 5, 1963, now Patent No. 3,194,811.

This invention relates to new chemical compounds. More particularly, itrelates to a new class of compounds of the benz-indole series. Stillmore particularly, it is concerned with new 1,3,4,5-tetrahydrobenz-[c,d]-indole-3- carboxylic acids and 1,3,4,5-tetrahydro-5-oxobenz-[c,d]-indole-3-carboxylic acids having an aromatic carboxylic acyl(hetero-aroyl) radical of less than three fused rings attached to thenitrogen atom of the indole ring. It is concerned further with salts,esters and amide derivatives of such compounds. It relates also to thesynthesis of such substances.

The new hetero-aroyl 1,3,4,5-tetrahydrobenz[c,d]-indole-3-carboxylicacid and 1,3,4,5-tetrahydro-5-oxobenz- [c,d]-indole-3-carboxylic acidcompounds of this invention have the general structural formula:

in which X is methylene or carbonyl, A is an aromatic carboxylic acylradical, i.e., a hetero-aroyl radical of less than three fused rings,and M is a group which provides an acid, ester, amide, anhydride or saltof the benz-indole.

In its more narrow aspects, the present invention embraces 1,3,4,5tetrahydrobenz[c,d] indole-3-carboxylic acids and derivatives thereofhaving the structural formulas:

C OM

and

COM

wherein Het is an aromatic heterocyclic ring having less than threefused rings, such as a fiveor six-membered heteroaromatic ring, forexample, furyl, thienyl, purryl, thiazolyl, thiadiazoyl, pyazinyl,pyridyl, alkylpyridyl, pyrozolyl, imidazoyl, oxazoyl, pyrimidinyl andisoxazoyl rings; and benz derivatives thereof;

3,336,307 Patented Aug. 15, 1967 R is hydrogen or a hydrocarbon radicalhaving less than nine carbon atoms, such as alkyl, for example, methyl,ethyl, propyl, isopropyl, butyl, and isobutyl; aryl and substitutedaryl, such as phenyl, alkoxyphenyl, for example, p-methoxyphenyl,p-ethoxyphenyl, mbutoxyphenyl, o-propoxyphenyl, 2,4-dimethoxyphenyl,3,4-dimethoxyphenyl and 3,4,5-trimethoxyphenyl and, for example,p-chlorophenyl, p-bromophenyl, p-fluorophenyl, 3,4-dich1orophenyl and2,3,4-trichlorophenyl; aralkyl, such as benzyl, p-methoxybenzyl,halobenzyl and the like; and

M is hydroxyl; amino, substituted amino, such as alkylamino, such asmethylamino, ethylamino and butylamino; dialkylamino, such asdimethylamino and diethylamino; allylamino, phenethylamino,N-ethylphenethylamino, benzylamino, aniline, p-chloroaniline,pmethoxyaniline; hydroxylated amino, such as diethanolamino; ringamino,such as piperidino, pyrrolidino, morpholino, l-methylpiperazino,N-phenylpiperazino, 1-6 hydroxyethyl piperazino, 1-methyl-2-aminomethylpyrrolidino, 1-ethyl-2-a1ninomethyl piperidino, tetrahydrofurfurylamino,N-phenylpiperazino, 1,2,5,6-tetrahydropyridino;n-carbobenzyloxymethylamino, and N,N dimethylcarboxamidomethyl; alkoxy,alkoxyalkoxy, aroxy, aralkoxy, alkaroxy, cycloalkoxy and alkenyloxy,including methoxy, ethoxy, n-butoxy, tbutoxy, ethoxyethoxy, phenoxy,benzyloxy, diphenylmethoxy, triphenylmethoxy, cyclopropoxy,fi-diethylamino, B-dimethylaminoethoxy, phenethoxy, allyloxy,isopropoxy, N-B-hydroxyethylmorpholine, cyclopropylmethoxy andtetrahydrofurfuryloxy; and CY where Y is a cation, or

In the most preferred compounds of the invention R is a lower alkyl,lower alkoxy, lower alkenyloxy, halogen, nitro, amino or substitutedamino. Examples of the alkyl and alkoxys are methyl, ethyl, propyl,t-butyl, methoxy, ethoxy, allyloxy, i-propoxy and the like. R is notlimited to this class of substituents, however, and may, if desired,

represent hydrogen or substituents, such as aryl, aralkoxy, such asbenzyloxy, hydroxy, mercapto, haloalkyl, such as CF CHF or otherhaloalkyls, nitro, amino, alkylamino, acylamino, haloalkyl, cyano,sulfamyl, sulfoxide, aminomethyl, substituted amino methyl, carboxy,N,N-dialkylcarbamyl and carboalkoxy groups.

A critical feature of the new compounds described herein is the presenceof the heterto-aroyl radical attached to the N-l position of the indole.This hetero-aromatic group may be substituted with hydrocarbon groups orwith functional substituents. The hetero-aromatic ring may contain, andin the preferred compounds does contain, at least one functionalsubstituent. This substituent may be a hydroxy or an etherified hydroxy(hydrocarbonoxy) group, such as a lower alkoxy, e.g., methoxy, ethoxy,isopropoxy, allyloxy, propoxy, an aryloxy or aralkoxy group, e.g.,phenoxy, benzyloxy, halobenzyloxy, lower alkoxybenzyloxy and the like.It may be a nitro radical, a halogen, such as chlorine, bromine, iodineor fluorine, an amino group or a substituted amino group, representativeexamples of which that might be mentioned are acylamino, amine oxide,urethanes, lower alkylamino, lower dialkylamino, amidine, acylatedamidines, alkoxyamines and sulfonated amines. Further, it may be amercapto or a substituted mercapto radical, exemplified by .of thepresent invention. Esters, salts, amides and an- 3 4 alkylthio groupsand their sulfoxides, such as methylthio, acid with the appropriateorganic base. The amides inethylthio, propylthio and their sulfoxidesand arylthio cluded within this invention are conveniently synthesizedor aralkylthio groups, e.g., benzylthio and phenylthio. by firstpreparing the amide of an l,3,4,5-tetrahydrobenz- The N-l hetero-aroylradical may, if desired, be halo- [c,d]-indole-3-carboxylic acidunsubstituted at the l-posialkylated, as with a trifluoromethyl,trifluoroethyl, per- 5 tion and then acylating said compound by theprocess fiuoroethyl, fl-cholorethyl or like substituent, acylateddescribed hereinbelow. Such amides are conveniently 0bas with acetyl,propionyl, benzoyl, phenylacetyl, trifluorotained by reacting the freeacid with urea or treating the acetyl and like acyl groups, or it maycontain a haloalkoxy appropriate acid chloride with ammonia or analkylamide or haloalkylthio substituent. In addition, the invention (toform an N-alkylamide). embraces compounds wherein the hetero-aroylradical The 2-position of the benz-[c,d]-indole ring nucleus contains asulfamyl, benzylthiomethyl, cyano, sulfon- (R in Formulas 'II and IIIabove) may be hydrogen amido or dialkylsulfonamido radical. Further, itmay although it is preferred that there be present at this contain acarboxy substituent, or a derivative thereof, position of the molecule ahydrocarbon radical having such as an alkali metal salt or a lower alkylester of the less than nine carbon atoms. Lower alkyl groups, suchcarboxy radical, an aldehyde, amide, and the like or an as methyl,ethyl, propyl or butyl are the most satisfactory aldehyde derivative ofthe type represented by acetals but aryl and substituted aryl may beused as well.

or thioacetals. In the preferred compounds, the N-l The followingcompounds are representative of those hetero-aroyl radical isisonicotinoyl and the functional contemplated by this invention andwhich may be presubtituent is in the para position of the six-memberedpared by the procedure discussed hereinbelow:

ring.

1-4'-thiazolyl-2-methyl-6-methoxy-1,3,4,5-tetrahydrobenz-[c,d]-indole-3-carboxamide;

1-2-thenoyl-2,G-dimethyl-1,3,4,5-tetrahydrobenz-[c,d]-indole-3-carboxylic acid;

1-2'-furoyl-2,6-dimethyl-1,3,4,5-tetrahydro-5-oxobenz-[c,d]-indole-3-carboxylic acid and the like.

The 1,3,4,5-tetrahydrobenz-[c,d]-indole 3-carboxylic acids andl,3,4,5-tetrahydro 5 oxobenz-[c,d]-indole-3- carboxylic acids describedherein are the primary objects hydrides of such carboxylic acidsrepresent an additional aspect of the invention. The esters areimportant intermediates in the synthesis of the free acids, and in manyThe tetrahydmbenz cases are, themselves, of importance as end products.dole3'carboxyhc F and the corresPondmg Among the preferred esters arethe lower alkyl esters, compolinds and denfatlves threof descllbedherein are Such as the methyl, ethyl propyl or t buty1 compoundssynthesized from an 1 ndole having the desired substituents and thebenzyl and like estem at the 2- and 5-pos1t1ons of the 1ndole ringnucleus, hav- The salts of these new l-hetero-aroyl 1,3,4,5-tetrahymgthe formula:

drobenz-[c,d]-indole-3-carboxylic acids and the corresponding S-oxocompounds can be obtained by treatment of the free acid with base undermild conditions. In this manner there may be obtained alkaline metalsalts, such \N as the sodium and potassium, the aluminum or magnesiumsalts or salts of alkaline earth metals, examples where R and R are asdefined above. The starting indole of which are barium and calcium.Salts of organic amines, compounds may be prepared as described innumerous h as dimethylan line, morpholinei methyl cyclohexylplaces inthe literature as, for example, in US. Patents amine or glucosamme maybe obtained by reacting the Nos. 2,825,734 and 2,708,197.

FLOW SHEET FOR SYNTHESIS OF'l-HETERO-AROYL-1,3,4,5-TETRAHYDR0BENZ-[c,d]-INDOLE-3 CARBOXYLIC ACIDSCH2-C O OH CH: 0 n Ru CHz-C O OH Rg- (1H--C -R1 R! RI 0 N If N H H lieII III IV C 0 OH O O OH O O OH Rg- Ru Ru R2 N \N R7 \N R! tic J|7=O HotV VI IV C O OH O O OH Br:

R \III 1 R! H b: lot

IX XI Generally the indoles are prepared by condensing a substitutedphenyl hydrazine with an aliphatic carbonyl compound to produce thecorresponding phenyl hydrozone which is cyclized to form the desiredindole. Other processes are presented in the aforementioned patents. Forexample, Z-methyl-5-trifluoromethylindole may be prepared as follows:

The treatment of the starting material according to the process of thepresent invention is summarized in the flow sheet (page 9).

The first step in the process of the present invention (Step A) is thecondensation of'the starting indole with maleic anhydride or maleic acidaccording to the pro cedure described by Diels and Alder in Ann. 490,277(1931). The reaction is carried out by mixing the constituents, suitablyin the absence of a solvent, with water bath heating until the mixturebegins to solidify. The mixture is then made basic and heated again withagitation, cooled and the product extracted with ether. In a typicalrun, 2- methyl-3-indolesuccinic acid (III R =CH R =H) is prepared byreaction of 2-methyl indole (II R =CH R =H) and maleic acid.

The next step in the procedure of preparing the compounds of the presentinvention is the dehydration of the indolyl succinic acid (III) to thecorresponding anhydride (IV), (Step B). Suitably this step is carriedout by reaction of acid with an isopropenyl lower alkanoate, as forexample, isopropenyl acetate, isopropenyl formate, isopropenylpropionate or isopropenyl butylate, in the presence of an acid catalyst.During this reaction the nitrogen atom of the indole ring issimultaneously acylated to produce the N-lower aliphatic acylderivative. For example, 1- acetyl-Z-methyl-3-indolesuccinic anhydrideis prepared by reaction of 2-methyl-3-indo1esuccinic acid withisopropenyl acetate in the presence of p-toluene sulfonic acid. Thereaction is advantageously carried out in an inert solvent which can beconstituted by an excess of the isopropenyl acetate. Other acidcatalysts which may be used include methane sulfonic acid, sulfuric acidand acid ion exchange resins. The acetone by-product formed during thereaction is removed by distillation and the desired product is recoveredfrom the solution in any convenient manner, as for example, bycrystallization from a suitable I AlCl ZnCl BF SnCl, and the like, in aFriedel-Crafts solvent, for example, ethylene dichloride,sym-tetrachloroethane, nitrobenzene or carbon disulfide. The reaction iscarried out at ambient temperature with or without cooling, as desired.The quantity of each reactant can vary by a large amount withouteffecting the course of the reaction. Ordinarily about 2-5 moles of thecondensation agent is used for each mole of anhydride. The reactionmixture is ,cooled and treated with a strong acid as, for example,sulfuric acid, phosphoric acid, or concentrated hydrochloric acid toprecipitate the product which then is recovered from the reactionmixture by crystallization.

The cyclization step produces a 5-oxo derivative of a1,3,4,5-tetrahydrobenz-[c,d] -indole-2-carboxylic acid (V).

In a typical reaction, 1-acetyl-2-methyl-3-indolesuccinic anhydride iscyclized to produce 1-acetyl-1,3,4,5-tetrahydro-5-oxobenz-[c,d]-indole-3-carboxylic acid.

At this point in the procedure the acetyl group may be hydrolyzed toproduce the corresponding compound unsubstituted at the nitrogen atom ofthe indole ring (VI) (Step D). Hydrolysis can proceed in a manner whichis known in the art as, for example, basic or acid hydrolysis as, forexample, in potassium hydroxide or hydrochloric acid solution to producethe compound VI. For example, in this stepl-acetyl-Z-rnethyl-l,3,4,5-tetrahydro-5-oxobenz-[c,d]-indole-3-carboxylicacid is hydrolyzed to produce 2-methyl-1,3,4,5-tetrahydro-5-oxobenz-[c,d] -indole- 3-carboxylic acid.

Once the 5-oxo intermediate is obtained in this manner, it can bedirectly hetero-aroylated to produce the desired l-hetero-aroyl-S-oxo(VIII) final product. This reaction can be carried out upon the acid orupon the ester or amide derivative which has the desired substituents inthe 2- and 6-positions of ring nucleus. It is preferred to carry out thehetero-aroylation on an ester or amide derivative of the car-boxylicacid. In those cases where the free acid is desired, the ester may thenbe converted to suitable conditions to the free acid. It has beenobserved that the l-hetero-aroyl substituent is easily hydrolyzed underconditions normally employed for saponification of an ester to the freeacid. For this reason, care must be taken in converting thel-hetero-aroyl derivative of 1,3,4,5- tetrahydro-S-oxobenz- [c,d]-indole-3-carboxylic acid esters to the corresponding free acids. It hasbeen found that one convenient method of accomplishing this conversioncomprises acylation of the benzyl ester and subsequent hydrogenolyticremoval of the benzyl ester. Alternatively, the esters, such as thet-butyl esters, which are amenable to selective removal by othertreatment, such as heating above 200 C. or by heating at 25-110 C. inthe presence of a catalytic amount of an aryl sulfonic acid or otheracids may be utilized. When, instead of an ester, the amides of theseacids are prepared, the free acids are formed by reaction of the amideswith a stoichiometric quantity of nitrous acid in an inert solvent. Theheteroaroylation reaction is preferably conducted by treatment of thebenz-[c,d]-indole-3-carboxylic acid material with an alkali metalhydride, such as sodium hydride, to form, e.g., a sodium salt and thenintimately contacting said salt with a hetero-aroyl acid halide in ananhydrous solvent medium. It is preferred to employ solvents such asdimethylformamide, 1,2-dimethoxyethane tetrahydrofuran,dimethylformamide benzene, benzene, toluene or xylene. It is preferredalso to carry out the acylation at about room temperature although lowertemperatures may be employed if the particular reactants are undulysusceptible to decomposition.

An alternative method of hetero-aroylation of the 1- position is by useof a phenolic ester of the acylating acid, such as the p-nitrophenylester. This latter is prepared by mixing the acid and p-nitrophenol intetrahydrofuran and adding dicyclohexyl carbodiimide in tetrahydrofuranslowly. The dicyclohexylurea which forms is removed by filtration andthe nitrophenyl ester is recovered from the filtrate. Alternatively,there can also be used the anhydride, azide or thiophenolic ester or thearoylating acid. Whichever is used, hetero-aroylation of thebenz-[c,d]-3-carboxy1ic acid material is achieved by forming a sodiumsalt of said material with sodium hydride in an anhydrous solvent andadding the nitrophenyl ester.

As described, the hetero-aroylation (Step E) produces the correspondingl-hetero-aroyl derivatives of 1,3,4,5- tetrahydro 5 oxobenz [c,d]indole-3-carboxylic acid. Compounds without the 5-oxo group can beprepared from (V) by simultaneous reduction of the l-acetyl and S-ketogroups by the Huang-Minlon procedure (Step F) followed byhetero-aroylation as before (Step E) Accordingly, the 0x0 acid isconverted to a salt thereof and then reduced with hydrazine hydrate. Thereduction is advantageously carried out in an inert solvent, forexample, dimethylsulfoxide, diethyl glycol or triethyl glycol, atelevated temperatures. The desired 1,3,4,5-tetrahydrobenz[c,d]-indole-3-carboxylic acid (XI) then is obtained by acidification ofthe reaction mixture followed by extraction and crystallization. Forexample, 2-methyl-1,3,4,5- tetrahydro oxobenz-[c,d]-indole-3-carboxylicacid is reduced to formZ-methyl-1,3,4,5-tetrahydnobenz-[c,d]-indole-3-carboxylic acid which isthen hetero-aroylated to produce the desired l-hetero-aroyl derivativeof Z-methyl- 1,3 ,4,5-tetrahydrobenzc,d -indole-3 -carboxylic acid.

An alternative procedure for preparing the succinic acid intermediate(III) starts with the 3-indole carboXaldehydes which are prepared byreaction of an indole unsubstituted in the 3-position with dirnethylformamide in the presence of phosphorous oxychloride. The processinvolves condensation of the 3-indole carboxaldehydes with ethylcyanoacetate or diethyl malonate, followed by reaction with potassiumcyanide in ethanol to produce a cyano derivative which is hydrolyzedwith aqueous potassium hydroxide to produce (III).

The l-hetero-aroyl l,3,4,5 tetrahydrobenz [c,d] indole-3-carboxylic acidand the corresponding S-oxo compounds have a high degree ofantiinfiammatory activity and are effective in the prevention andinhibition of granuloma tissue formation. Certain of them possess thisactivity in high degree and are of value in the treatment of arthriticand dermatological disorders and in like conditions which are responsiveto treatment with antiinflammatory agents. In addition, the compounds ofthis invention have a useful degree of antipyretic and analgesicactivity. For these purposes, they are normally administered orally intablets or capsules, the optimum dosage depending, of course, on theparticular compound being used and the type and severity of infectionbeing treated. Although the optimum quantities of these com-pounds ofthis invention to be used in such manner will depend on the compoundemployed and the particular type of disease condition treated, oral doselevels of preferred compounds in the range of 1.0-2000 mg. per day areuseful in control of arthritic conditions, depending on the activity ofthe specific compound and the reaction sensitivity of the patient.

The synthesis of various compounds of this invention having on thebenz-indole ring system a 6-substituent which has a nitrogen attached tothe aromatic homocyclic ring of the benz-indole is generally based onthe 6-nitro compound. This is transformed into the desired6-substituent. Such transformation may be made before or afterhetero-aroylation of the l-position, depending on the extent to whichthe desired 6-substituent may interfere with the acylation. If suchinterference is possible, the l-acylation should be carried out on the6-nitro benzindole and the nitro later transformed into the desiredG-substituent. Such transformation can be carried out in a number ofways. Suitably nitration can be effected on an N,N-dialky1 substitutedamide of the benz-indole followed by acylation. Reduction of the 6-nitrogroups gives a 6-amino group. Reaction of the amino with alkyl halidesgives mono and dialkyl amino groups. If the alkyl halide is adihaloalkylene group (e.g., 1,4-dibromobutane), a heterocyclic ring(e.g., pyrrolidino) is formed. Similarly, bis(B-chlorethyl)ether willgive an N-morpholino compound. Alkylation can also be carried outsimultaneous with reduction, as e.g. with formaldehyde and Raney nickeland hydrogen. Acylation can similarly be carried out on the 6-aminocompounds on the 6-nitro (with simultaneous reduction) to give6-acylamido compounds. The 6-amino group can be reacted with isocyanatesto give 6-ureido compounds.

Compounds where R is OH are prepared by starting an indole where R isbenzyloxy and reducing the final compound substituted with a benzyloxygroup to produce the corresponding hydroxy substituted compoundaccording to the procedure in the aforementioned US. Patent 2,825,734.

As mentioned, R is preferably hydrogen, allyloxy, fiuoro, methyl,trifluoromcthyl, benzyloxy, methoxy or dimethyl sulfamyl. All of theabove R groups do not contain an active hydrogen and therefore do notinterfere with the hetero-aroylation step. When nitro (from which amino,dimethyl amino and acyl amino are obtained) is desired in position 6 ofthe ring, it is preferable that the cyclization be carried out in theabsence of a nitro group on position 6. Then the cyclized compound isnitrated to produce the corresponding compound where R is nitro.

Where the hetero-aroylation ester or amide itself is desired as a finalcompound, the acid (VI) or (IX) may be directly converted to the desiredester in a variety of reaction sequences, as for example, formation ofthe acyl chloride and reaction with alcohol or direct reaction withalcohol, or with diazomethane or a substituted diazomethane, or in otherways known in the art as for example, with the carbodimide describedabove, and this ester hetero-aroylated in the manner described above.This techniques is particularly advantageous for those esters and amideswhich do not contain an active hydrogen as for example, the methylester, the diethyl amino ethyl ester, and the morpholinyl amide. On theother hand, hetero-aroylation of esters and amides which contain anactive hydrogen in the ester or amide moiety as, for example, thecarboxamide or the hydroxy ethyl carboxamide, is carried out, forexample, on the tertiary butyl ester which is then pyrolyzed to form theacid. Esterification or amidation then can be performed on the heteroaroylated acid.

The following examples are given for purposes of illustration and not byway of limitation:

EXAMPLE 1 Preparation of 1- (3-fur0yl)-2-methyl-1,3,4,5-tetrahydrobenzc,d] -ind0le-3-carboxylic acid (A)2-methyl-3-ind0lesuccinic acid.A mixture of 0.1

mole of Z-methylindole and 0.1 mole of maleic acid is heated on a steambath until the bottom of the mixture begins to solidify. The flask thenis removed from the bath and allowed to stand for 30 minutes. A solutionof 11.3 g. of potassium hydroxide in 200 ml. of water is added and themixture is heated on a steam bath with agitation for one-half hour.After cooling, the solution is extracted with ether to remove anyneutral material treated with charcoal, filtered, cooled, and acidifiedwith hydrochloric acid. The precipitate is collected on a filter andwashed with cold water to give 2-methyl-3-indolesuccinlc acid; M.P.210-21l C. (decomposition),

(B) I-acetyl-Z-methyl 3 indolesuccinic anhydride.- A mixture of 0.1 moleof 2-methyl-3-indolesuccinic acid, 200 ml. of isopropenyl acetate and 2g. of p-toluenesulfonic acid monohydrate is heated under refiux foronehalf hour. The acetone is then removed by fractionation slowlythrough a Vigreux columun until the boiling point reaches C. Thesolution is then evaporated in vacuo and the residue is crystallizedfrom a mixture of 60 ml. acetic acid and 15 ml. acetic anhydride to givea M.P. of 192-193 C.

(C) 1 acetyl 2 methyl ],3,4,5 tetrahyld'ro 5-oxobenz-[c,d]-ind0le-3-carb0xylic acid.-The anhydride of (B) 0.01 moleis dissolved in 60 ml. of Warm ethylene dichloride. The solution iscooled with agitation until the ambient temperature provides a finesuspension. To a suspension of 0.01 mole of the above anhydride in 60ml. of ethylene dichloride at room temperature is added 0.05 mole ofaluminum chloride. The mixture is heated on a steam bath for two hours,cooled by addition of ice, and a solution of 50 ml. 2 N hydrochloricacid is added. The precipitate is filtered, washed with water andredissolved in warm acetone. The solution is treated with decolorizingcharcoal and cooled in a refrigerator to produce1-acetyl-2-methyl-1,3,4,S-tetrahydro-S-oxobenz[c,d]-

9 indole-3-carboxylic acid as yellow needles; M.P. 215- 217 C.

(D) 2 methyl 1,3 1,5 tetrahydrobenz [c,d] indle-3-carboxylic acild.-Asolution of 1 g. l-acetyl oxo acid obtained in (C) and 50 ml. of 0.2 NNaOH is allowed to stand at room temperature for three hours afteracidification with diluted HCl, the precipitated product is filtered,washed with water and recrystallized from dilute acetic acid to give2-methyl-1,3,4,5-tetrahydro-5-oxobenz- [c,d]-indole-3-carboxylic acid,M.P. 235239 C. (dec.).

(E) 2 methyl 1,3,4,5 tetrahydr0benz-[c,d] indole- 3-carb0xylz'c acid.Thel-acetyl-S-oxo acid 0.1 mole obtained in (C) and hydrazine hydrate (0.5mole 85% solution) is added at room temperature to a cooled solution ofsodium hydroxide (0.5 mole) in 250 ml. of diethylene glycol. The mixtureis heated under reflux for 20 minutes, cooled, diluted with 500 ml. ofwater and then extracted with ether. The aqueous solution is cooled inan ice-bath, acidified with concentrated HCl, and extracted with ether.The ethereal extract is washed with water, dried over anhydrous sodiumsulfate and evaporated in vacuo. The residue is dissolved in chloroformand treated with charcoal, filtered, concentrated and cooled. There isthus obtained Z-methyl-l,3,4,5-tetrahydrobenz-[c,d]-3- indole-carboxylicacid as yellow plates M.P. 173l74 C.

(E-l) 2 methyl 1,3,4,5 tetrahydro benz [c,d]-indole-3-carb0xylicanhydride.Dicyclohexylcarbodimide (10 g., 0.049 mole) is added to asolution of Z-methyl- 1,3,4,5 tetrahydro 5 oxobenz [c,d] indole 3carboxylic acid in 200 ml. of THF, and the solution is allowed to standat room temperature for two hours. The precipitated urea is removed byfiltration, and the filtrate is evaporated in vacuo to a residue andflushed with Skellysolve B. The residual oily anhydride is used withoutpurification in the next step.

(E2) t-Butyl 2-methyl-1,3,4,5-tetrahydrobenz-[c,d]-indole-.i-carboxylate.t-Butyl alcohol (25 ml.) and fused zinc chloride(0.3 g.) are added to the anhydride from part E-l. The solution isrefluxed for 16 hours and excess alcohol is removed in vacuo. Theresidue is dissolved in ether, washed several times with saturatedbicarbonate, water and saturatedsaltsolution. After drying overmagnesium sulfate, the solution is treated with charcoal, evaporated,and flushed several times with Skellysolve B for complete removal ofalcohol. The residual oily ester is used without purification.

(E-3) t-Butyl1-(3-fur0yl)-2-methyl-I,3,4,5-tetrahya'robenz-[c,d]-ind0le-3-carboxylate.-Astirred solution of the ester from E-2 (0.08 mole) in dry DMF (450 ml.)is cooled to 4 C. in an ice bath, and sodium hydride (4.9 g., 0.098mole, 50% susp.) is added in portions. After 15 minutes, 3-furoylchloride (0.085 mole) is added dropwise during minutes, and the mixtureis stirred for 9 hours without replenishing the ice bath. The mixture isthen poured into 1 liter of 5% acetic acid, extracted with a mixture ofether and benzene, washed thoroughly with water, bicarbonate, saturatedsalt, dried over magnesium sulfate, treated with charcoal, andevaporated to a residue. The crude product is chromatographed on acolumn of 300 g. acid-Washed alumina using ether-petroleum ether (v./v.20100%) as solvent.

(E4) 1 (3 furoyl) 2 methyl 1,3,4,5tetrahydrobenz-[c,d]-indole-3-carboxylic acid.A mixture of 1 g. of thet-butyl ester from (E-3) and 0.1 g. powdered porous plate is heated inan oil bath at 210 C. with magnetic stirring under a blanket of nitrogenfor about 2 hours. No intensification of color (pale yellow) occursduring this period. After cooling under nitrogen, the product isdissolved in benzene and ether, filtered, and extracted withbicarbonate. The aqueous solution is filtered with suction to removeether, neutralized with acetic acid, and then acidified weakly withdilute hydrochloric acid. The crude product is recrystallized fromaqueous ethanol and dried in vacuo at 65 C.

1 0 EXAMPLE 2 The procedure of Example 1 is followed, using equalquantities of the following starting materials in place of2-methyl-indole: Z-methyl-S-methoxy-indole; Z-methyl- 5 methyl indole; 2methyl 5 benzyloxy indole; 2 phenyl 5 methoxy indole; 2 p methoxyphenol-5-methox-y-9-indole; Z-methyl-S-fluoro-indole; 2-ethyl-5- methyl indole;2 ,6 chlorophenyl 5 chloro indole; S-methoxy-indole; S-benzyloxy-indole;S-methyl-indole; S-ethoxy-indole; 2-benzy1-S-methoxy-indole, there areobtained the following corresponding final products:

1- 3 '-furoyl) -2-methyl-6-anethoxy- 1,3 ,4,5-tetrahydrobenz- [c,d]-indole-3-carboxylic acid;

1-( 3 -furoyl) -2-methyl-6-methyl-1,3,4,5-tetrahydrobenz- [c,d]-indole-3-carboxylic acid;

1-(3'-furoyl)-2-methyl-6-benzyloxy-1,3,4,5-tetrahydrobenzc,d] -indole-3-carboxylic acid;

l- (3 '-furoyl) -2-phenyl-6-methoxy- 1,3 ,4,5-tetrahydrobenz- [c,d]-indole-3-carboxylic acid;

1- (3 '-furoyl) -2-p-methoxyphenol-6-methoxy-1,3 ,4,5-tetrahydrobenz-[c,d] -indole-3-carboxylic acid;

1-(3-furoyl)-2-methyl-6-fluoro-1,3,4,5-tetrahydrobenz-[c,d]-indole-3-carboxylic acid;

1- 3 -furoyl -2-ethyl-6-methyl-1,3 ,4,5 -tetrahy drob enz-[c,d]-indole-3-carboxylic acid;

l- (3 '-furoyl)-2-chlorophenyl-6-chloro-1,3,4,5-tetrahydrobenz-[c,d]-indole-3-carboxylic acid;

1-(3-furoyl)-6-methoxy-1,3,4,5-tetrahydrobenz-[c,d]-

indole-3-carboxylic acid.

EXAMPLE 3 The procedure of Examples 1 and 2 is followed using equivalentquantities of the following hetero-aroyl chlorides in place of 3-furoylchloride: 1-methy1imidazol-5 carboxylic acid chloride,1,3-dimethyl-2,3-dihydro-2- oxoimidazole-4-carboxylic acid chloride,l-methylbenzimidazol-Z-carboxy chloride, 5-fluoro-2-thenoyl chloride,3-thenoyl chloride, 5-nitro-2-furoyl chloride,l-methylindazole-3-carboxy chloride, 1-methyl-6-nitroindazole-3- carboxychloride, oxazole-4-carboxy chloride, benzoxazole 2 carboxy chloride,thiazole-4-carboxy chloride, thiazole-Z-carboxy chloride,2-phenylthiazole 4 carboxy chloride and2-benzylmercaptothiazole-4-carboxy chloride to produce the correspondingN-l hetero-aroyl derivatives of the 2 and 6 substituted1,3,4,5-tetrahydrobenz-[c,d]-indole-3-carboxylic acids produced inExamples 1 and 2.

EXAMPLE 4 (A) p-Nitrophenylisonicotinate.ln a 500 ml. round bottom flask(all equipment flame dried) is added 13.9 g. of p-nitrophenol and 12.3g. isonicotinic acid in 250 ml. drly tetrahydrofuran. Through a droppingfunnel is added over 30 minutes 20.6 g. of dicyclohexylcarbodiimide inml. of dry tetrahydrofuran. The reaction is allowed to run overnightwith stirring. The dicyclohexylurea which forms during the reaction isfiltered. The filter cake is Washed with dry tetrahydrofuran. Thesolution is evaporated to dryness. The solid is taken up in benzene andwashed with sodium bicarbonate solution and then with water and driedover anhydrous sodium sulfate. The solution is concentrated under vacuumto dryness. The solid p nitrophenylisonicotinate is then recrystallizedfrom benzene, M.P. 126-127 C.

i (B) t-Butylisonicotinoyl-Z-methyl-6-meth0xy-1,3,4,5- tetrahydrobenz[c,d] indole 3 carboxylate.-In a 250 ml. round bottom flask (flame driedequipment) is placed at 0 C. with nitrogen, 100 ml. of drydimethylformamide with 10.5 g. of t-butyl-2-methyl-6-methoxy- 1,3,4,5-tetrahydrobenz-[c,d]-indole-3-carboxylate. To this is added 2.5 g. of50% sodium hydride mineral oil mixture. After the mixture is stirred for30 minutes,

there is added over 15 minutes a solution of 11 g. ofp-nitrophenylisonicotinate in 50 ml. dry dimethylformamide. The reactionmixture is stirred for 4 hours at C. under nitrogen followed by stirringunder nitrogen at room temperature overnight. The reaction mixture isthen poured into an ice-water ether solution containing a few ml. ofacetic acid and the layers are separated. The aqueous phase is washedwith ether and the ether extracts are combined. To the ether layers isadded a saturated solution of hydrogen chloride gas in dry ether. Theether is decanted off, leaving a heavy oil. The oil is washed with etherfollowed by an addition of aqueous sodium bicarbonate solution. Theproduct is then extracted with ether. The ether layer is dried overanhydrous sodium sulfate and concentrated to dryness. The product iscrystallized from dry ether.

(C) To obtain the desired acid product, the t-butyl ester obtained in(B) is pyrolyzed according to Example 1 (E-4).

EXAMPLE (A) The procedure of Example 4A is followed using an equivalentamount of the following acids in place of isonicotinic acid to producethe corresponding p-nitro phenyl esters: 1-methylpyrryl-Z-carboxylicacid, S-methylpyrazole-3-carboxylic acid,1,5-dimethyl-4-bromopyrazole-3-carboxylic acid, l-phenylpyrazole 4carboxylic acid, 1-phenyl-5-pyrazolone-3-carboxylic acid; 2-phenyl-5-methyloxazole-4-carboxylic acid, isoxazole-3-carboxylic acid,5-phenyl-isoxazole-3-carboxylic acid, 1,2-benzoisothiazole-3-carboxylicacid, 1,2,3 thiadiazole-4-carboxylic acid,l-methyl-l,2,3-triazole-4-carboxylic acid, nicotinic acid, picolinicacid, isonicotinic acid-N-oxide, 3-chloroisonicotinic acid,6-methoxynicotinic acid, 6-phenylnicotinic acid, a-pyrone-S-carboxylicacid, pyridazine-4-carboxylic acid,3-keto-4-methyl-2-phenyl-2,3-dihydropyridazine 6 carboxylic acid,cinnoline-4-carboxylic acid, 2 methylmercapto 4 chloropyrimidine 5carboxylic acid, 2,4-dichloropyrimidine-5-carboxylic acid, pyrazinoicacid, and S-methoxy-pyrazinoic acid.

(B) The p-nitrophenyl esters so obtained are then employed tohetero-aroylate the product of Example 1 (E2) and Example 2 inaccordance with the procedure of Example 4B followed by pyrolysis inaccordance with Example 1 (E-4).

EXAMPLE 6 M ethyl-1 (3 -fur0yl) -2-methyl-1,3,4,5-tetrahydr0benz- [0,d]-ind0le-3-carb0xylate (A) Methyl-2-methyl-1,3,4,5tetrahydrobenz-[c,d]-indole-3 carboxylate.-To a solution of 0.1 mole of2- methyl-l,3,4,5-tetrahydrobenz-[c,d] indole-3-carboxylic acid and 0.2mole of triethylamine in 200 ml. of 1,2- dimethoxyethane is added 0.12mole of isobutylchloroformate dropwise with stirring and ice-cooling.After onehalf hour 0.1 mole of methanol in 30 ml. of dimethoxyethane isadded and the reaction mixture is stirred for an additional 46 hours.The mixture is filtered, concentrated in vacuo and poured into icewater. The product is extracted into ether, washed with sodiumbicarbonate and dried over Na SO Evaporation of the ether solution andchromatography of the residue on 300 g. of acid-washed alumina usingether-petroleum ether (v./v. -50%) gives the methyl ester.

The same ester is obtained by the treatment of the starting acid with 1equivalent of diazomethane in ether solution.

(B) The procedure of Example 1 (E-3) is followed using equivalentquantities of the methyl ester obtained in A above in place of thet-butyl ester to provide the desired methyl-'1-(3'-furoyl) derivative.

EXAMPLE 7 (A) The procedure of Example 6A is followed using equivalentquantities of the following alcohols in place of methyl alcohol: ethylalcohol, phenol, cyclopropyl al-' cohol, fl-dimethylamino ethanol,B-diethylamino ethanol, phenethyl alcohol, allyl alcohol, iso-propylalcohol, benzyl alcohol and N-B-hydroxyethyl morpholine, cyclopropylmethanol, n-butyl alcohol and tetrahydrofurfuryl alcohol and the acidsobtained in Examples 2 and 3 in place of 2-methyl-1,3,4,5-tetrahydrobenz[c,d] -indole-3-carboxylic acid to provide the corresponding esters ofthese acids.

(B) The procedure of Example 1 (E3) or Example 4B is followed usingequivalent quantities of the esters obtained in A above in place of thet-butyl ester to provide the desired corresponding ester derivatives ofthe acids of Examples 2 and 3.

EXAMPLE 8 The procedure of Example 6A is followed to convert thehetero-aroylated acids obtained in Examples 14 to the correspondingamides by reaction with an equivalent quantity of the following primaryand secondary amines and ammonia in place of the alcohols of Example 6A:allylamine, ethylamine, methylamine, dimethylamine, butylamine,diethylamine, phenethylamine, piperidine, N- ethylphenethylamine,pyrrolidine, benzylamine, morpholine, aniline, l-methylpiperazine,p-chloroaniline, p-methoxyaniline, l-B- hydroxyethyl piperazine, 1methyl-2- aminomethyl pyrrolidine, l-ethyl-2-aminomethyl piperidine,diethanolamine, tetrahydrofurfurylamine, l-phenylpiperazine,cyclohexylamine, 1,2,5,6 tetrahydropyridine, glycine, dimethylamine,fl-diethylamine and ammonia to produce the corresponding amides.

EXAMPLE 9 The hetero-aroylated acids obtained in Examples l-4 areconverted to the corresponding salts by reaction with a base as follows:A solution of 0.105 mole of the 1-(3'-furoyl)-1,3,4,5-tetrahydrobenz-[c,d]-indole 3 carboxylic acid in 100 ml.ethanol is mixed with 0.10 mole of Na ethoxide in 100 ml. ethanol withice-cooling and stirring. The solution is concentrated in vacuo, dilutedwith 500 ml. ether, and the sodium salt precipitated is collected on afilter, washed with ether, and dried in vacuo to provide the Na salt.

Similarly, when 0.10 mole of potassium t-butoxide, aluminumisopropoxide, triethylamine, B-diethylaminoethanol, choline andmorpholine are used, the corresponding potassium, aluminum,triethylamine, fi-diethylamine, ethyl, choline and morpholine salts areobtained.

Similarly, when other hetero-aroylated acids produced in Examples 1-4are utilized, the corresponding salts are obtained.

EXAMPLE 10 (A) 1-(3' furoyl)-2-methyl-I,3,4,5-tetrahydr0-5-0x0- benz-[c,d] -indole-3-carboxylic acid,2-met'hyl-1,3,4,5-tetrahyrdo-S-oxobenz-[qd]-ind0le-3-carboxylic acid.Asolution of 10 g. of 1-acetyl-2-methyl-l,3,4,5-tetrahydro-5-oxobenz-[c,d]-indo1e-3-carboxylic acid in 200 ml. ethanol containing 0.1mole of sodium hydroxide is stirred at room temperature for 4 hours. Themixture is concentrated in vacuo to ml., poured into iced water andacidified with dilute HCl to give the product.

(B) The procedure of Example 1 (E-4) is followed with 3-furoyl chlorideto hetero-aroylate the t-butyl ester of A above to produce the desired1-(3'-furoyl) derivative.

EXAMPLE 11 Following the procedure of Example 10 and using equivalentquantities of the following l-acetyl esters in place of1-acetyl-2-methyl-1,3,4,S-tetrahydro-S-oxobenz-[c,d]-indole-3-carboxylic acid; t-butyl-I-acetyl-Z-methyl- 6 methoxy1,3,4,5 tertahydrobenz-[c,d]-indole-3'carboxylate; and tbutyl-1-acetyl-2-methyl-6-benzyloxy-1,3, 4,5-tetrahydrobenz-[c,d]-indole-3-carboxylate, there is obtained the correspondinghereto-arolylated compounds.

l- (3-furoyl) -2-methyl-6-hy'droxy-1,3,4,5-tetrahydr0- benz- [c,d]-indle-3-carboxylic acid A mixture of 0.05 mole of1-(3-furoy1)-2-methyl-6- benzyloxy 1,3,4,5 tetrahydrobenz [c,d] indole3- carboxylic acid in 200 ml. of ethanol is hydrogenated overpalladium-carbon catalyst at 45 p.s.i. at room temperature until 0.05mole of hydrogen is absorbed. The mixture then is filtered, evaporatedin vacuo, chromatographed on a silica gel column (500 g.) usingether-petroleum (v./v. 50100%) as eluent. The solvent is evaporated andthe product recovered.

EXAMPLE 13 (A) To a solution ofN,N-dimethyl-1,3,4,5-tetrahydrobenz-[c,d]-indole-3carboxamide in 5 m1.acetic acid is added dropwise a solution of 0.6 ml. nitric acid (d.1.37) in 4 ml. acetic acid at room temperature with stirring. After 18hours the reaction mixture is poured into ice water and extracted withether. The ether solution is washed with water, sodium bicarbonate,dried over so dium sulfate and evaporated to a residue. The residue ischromatographed on a column of 30 g. acid-washed alumina usingether-petroleum ether (v.v. 30100%) as solvent. The structure of theproduct N,N-dimethyl-6- nitro 1,3,4,5 tetrahydrobenz [c,-d] indole3-carboxamide is established by N.M.R. Studies- (B) The procedure ofExample 1 (E4) is followed with 3-furoyl chloride to hetero-aroylate the6-nitro-1'r1- dole amide of A.

(C) 3 g. of product of (B) is dissolved in 300 ml. dry methanol andreduced in hydrogen in an autoclave with Raney nickel as catalyst. Afterthe theoretical amount of hydrogen is taken up, the catalyst is removedby filtration. The catalyst and reaction flask are washed with methanol.The methanol solution is evaporated to dryness. The product iscrystallized from benzene.

EXAMPLE 14 1-(3-fur0yl -2-mlethyl-6-methoxy-1,3,4,5-tetrahydr0- benz-[c,d] -ind0le-3-carboxylic acid anhydride (A) Dicyclohexylcarbodiimide(0.049 mole) is dissolved in a solution of 2-methyl-6-rnethoxy-1,3,4,5-tetrahydrobenz [c,d] indole 3-carboxylic acid (0.10 mole) in 200 ml. ofTHF, and the solution is allowed to stand at room temperature for 2hours. The precipitated urea is removed by filtration, and the filtrateis evaporated in vacuo to a residue and flushed with Skellysolve B. Theresidual oily anhydride is used without purification in the next step.

(B) The procedure of Example 1 (13-4) is followed using the anhydrideproduced in (A) to provide the 1-(3'- furoyl) derivative.

What is claimed is:

1. A compound of the formula wherein:

Het is selected from the group consisting of triazolyl,

furyl, thienyl, thiazolyl, thiadiazolyl, pyrazinyl, cinnolinyl, pyridyl,pyrazolyl, imidazolyl, oxazolyl, pyrimidinyl, pyrrolyl,dihydroimidazolyl, dihydropyridazinyl, isoxazolyl, benzimidazolyl,indazolyl, benzoxazolyl, pyrazolonyl, isothiazolyl, pyronyl,pyridazinyl, dihydropyridazinyl and dihydrooximidazolyl rings andsubstituted rings thereof wherein the substituent is selected from thegroup consisting of lower alkyl, dilower alkyl, halo, nitro, phenylbenzylmercapto, lower alkoxy, lower alkylthio, N-oxide and keto;

R is selected from the group consisting of hydrogen, lower alkyl,halophenyl, lower alkoxyphenyloxy, phenyl, benzyl, hydroxy, benzyloxyand lower alkoxy;

R is selected from the groupconsisting of hydrogen, lower alkyl, loweralkoxy, halogeno, hydroxy, di (lower alkyl)amino and benzyloxy;

X is selected from the group consisting of methylene and carbonyl; and

M is selected from the group consisting of hydroxy, amino, lower alkoxy,phenoxy, cyclopropoxy, di (lower alkyl)amino-lower alkoxy, phenyl loweralkoxy, lower alkenyloxy, lower alkylamino, di(lower alkyl)amirro,morpholino-lower alkoxy, tetrahydrofurfuryloxy, phenethylamino,N-ethylphenethylamino, benzylamino, anilino, p-chloroanilino,p-methoxyanilino, diethanolamino, piperidino, pyrrolidino, morpholino,l-methylpiperazino, N-phenylpiperazino, 1 B hydroxyethylpiperazino,l-methyl- 2-aminomethyl pyrrolidyl, 1-ethyl-2-aminornethyl piperidyl,tetrahydrofurfurylamino, N -phenylpiperazino,l,2,5,6-tetrahydropyridino, carbobenzoxymethylamino andN,N-dimethylcarbamylmethyl; and OY wherein Y is selected from the groupconsisting of a pharmaceutically acceptable non-toxic cation and \N R2 1Het where X, R R and Het are as defined above.

2. A compound of claim 1 wherein Het is pyridyl; R is lower alkyl; R islower alkoxy; and X is methylene.

3. A compound of claim 1 wherein Het is pyridyl; R is lower alkyl; R islower alkoxy; and X is carbonyl.

4. 1 isonicotinoyl 2methyl-6-methoxy-1,3,4,5-tetrahydrobenz-[c,d]-indolecarboxylic acid.

No references cited.

ALEX MAZEL, Primary Examiner.

JOSE TOVAR, Assistant Examiner.

1. A COMPOUND OF THE FORMULA
 3. A COMPOUND OF CLAIM 1